Abstract
HIV
Age-Related Diseases Increase in AIDS
Reconstitution of the immune system and improved survival among HIV-infected individuals on antiretroviral therapy (ART) is having an overall effect on patterns of morbidity and mortality among the HIV/AIDS population. The ongoing prospective, observational Swiss HIV Cohort Study group recently reported age-related diseases such as diabetes mellitus, cardiovascular disease, non-AIDS-related malignancies, and osteoporosis, are increasingly common among HIV-infected patients 65 years of age and older. Hazard ratios were particularly high for stroke (17.7), myocardial infarction (5.89), and bone fragility fractures (10.5). In addition to longer survival times related to ART, these co-morbidities may also be the result of toxicities related to long-term ART, chronic inflammation due to HIV infection, and lifestyle factors.
Source: Hasse B, Ledergerber B, Furrer H, et al. Morbidity and aging in HIV-infected persons: The Swiss HIV Cohort Study. Clin Infect Dis 2011;53:1130–1139.
New Guidelines for HIV Care
A panel convened by the International Association of Physicians in AIDS Care (IAPAC) has released evidence-based guidelines intended to optimize entry into and retention in care and ART adherence for HIV-infected individuals. The recommendations are based on 325 studies, cover monitoring of and interventions to improve entry and retention in care, strategies to improve ART adherence, and issues related to special patient populations.
“Clearly there is lots of room for improvement in how we, as care providers, can get new patients into treatment and help them adhere to the often strict drug regimens needed to suppress the viral disease and prevent drug resistance,” Dr. Larry W. Chang, a co-author of the guidelines and Assistant Professor at Johns Hopkins University told the Baltimore Sun newspaper. He noted that the death rate for HIV-infected patients who skip follow-up care within the first year of treatment is two times higher than for patients who adhere to a treatment regimen. Furthermore, he added that nearly 66% of patients with HIV/AIDS never receive optimal ART, only 59% stay on their regimen; and fewer than 33% achieve a suppressed or nearly suppressed viral load.
Source: Thompson MA, Mugavero MJ, Amica KR, et al. Clinical guidelines for improving entry into and retention in care and antiretroviral adherence for persons with HIV: Evidence-based recommendations from an International Association of Physicians in AIDS Care panel. Ann Intern Med 2012;e419.
Good and Bad News for HIV-infected IDUs
The Centers for Disease Control and Prevention (CDC) reported that HIV prevalence among intravenous drug users (IDUs) in the U.S. has dropped by 50%, from an estimated 18% based on 1993–1997 survey data to 9% in 2009. The new CDC findings reveal that 45% of IDUs who tested positive for HIV were unaware of their infection. Among the IDUs who were either HIV-negative or of unknown HIV status prior to the 2009 survey, 69% reported participating in high-risk sexual behaviors during the previous year, including unprotected vaginal sex (69%), sharing syringes (34%), and unprotected heterosexual anal sex (23%). During that 12-month period, only 49% of IDUs at risk for HIV infection were tested.
Source: Wejnert C, Pham H, Oster AM, et al. HIV infection and HIV-associated behaviors among injecting drug users—20 cities, United States, 2009. MMWR 2012;61:133–138.
HIV Does Not Discourage Youth Pregnancy
A study of predominantly African-American, HIV-infected, urban young women, aged 15–24 years, found that HIV status did not diminish their desire for a future pregnancy. Furthermore, the HIV-infected young females were significantly more likely to perceive that their partners would respond positively to a pregnancy, compared to the uninfected young women surveyed. The African-American young women were significantly more likely to share this perception than their white peers. Overall, though, race did not affect their expressed interest in childbearing. The authors concluded the following: “These data suggest that the desire for childbearing is not diminished by HIV infection among urban female youth, highlighting the need for routine, provider-initiated discussions about childbearing with urban youth to minimize unintended pregnancies and HIV transmission.”
Source: Finocchario-Kessler S, Sweat MD, Dariotis JK, et al. Childbearing motivations, pregnancy desires, and perceived partner response to a pregnancy among urban female youth: Does HIV-infection status make a difference? AIDS Care 2012;24:1–11.
New Disease Indicators for HIV Infection
About 2.5 million Europeans are HIV-infected, according to UNAIDS estimates, and as many as 900,000 are not aware they are HIV positive. Indicator diseases can be used to diagnose HIV-infected individuals earlier in the course of chronic HIV infection, begin treatment earlier, preserve and restore immune function, and reduce the risk of viral transmission. Jens Lundgren, Co-chair of the HIV in Europe Initiative, and Professor of Viral Diseases at the University of Copenhagen, reported on the findings of the HIV in Europe Initiatives' HIDES (HIV Indicator Diseases Across Europe) study that evaluated the link between either diseases not currently on the list of AIDS-defining diseases and whether they could serve as indicators (though not definitive signs) of hidden, undiagnosed HIV infection. The following diseases are associated with an increased incidence of HIV: a sexually transmitted infection; malignant lymphoma; cervical or anal cancer/dysplasia; herpes zoster; hepatitis B or C; ongoing mononucleosis-like illness; inexplicable, persistent decline in the number of circulating white blood cells; or seborrheic dermatitis/exanthema. The presence of these diseases “should encourage health care professionals to offer the patient an HIV test,” says Dr. Lundgren.
Source: Press release: Copenhagen HIV Programme (CHIP), University of Copenhagen, March 1, 2012.
Abstracts From the 19th Conference On Retroviruses And Opportunistic Infections, March 2012
Symposium–Pathways Toward a Cure: Viral Latency And Reservoirs
The main barriers to a cure for HIV infection are latent cell infection, persistent low-level virus replication, and anatomical reservoirs. Intensification of antiretroviral therapy does not appear to affect latent reservoirs. Clinical trials are underway with existing drugs—histone deacetylase inhibitors and methylation inhibitors—that have shown promise in vitro in reversing latency. Other strategies for HIV eradication in development include gene therapy to reduce expression of the HIV co-receptor CCR5 and interventions to reduce immune activation and boost HIV-specific immunity. Clinical testing of these strategies face several challenges: the need for better assays to quantify persistent virus in patients on ART, selection of clinical endpoints, risk/benefit considerations, and the need to be able to scale up effective interventions and make them available to low-income populations.
The risk/benefit issues associated with testing “functional cures” aimed at virus eradication creates an opportunity for evaluating these interventions in non-human primate models, but practical limitations have slowed their development. Significant progress has been made, however; multiple non-human primate models are being optimized, and studies have begun in ART-treated animals with suppressed plasma viremia with approaches to induce HIV expression in vitro and in vivo, together with various virologic monitoring strategies and safety studies.
New data from human studies of antiretroviral drug penetration into HIV reservoirs demonstrate drug-specific compartmentalization. Inadequate drug penetration may allow for cryptic HIV replication supporting sustained infection. This presentation included potential strategies to overcome pharmacologic sanctuaries.
The presentation reviewed ongoing and planned studies of novel interventions and agents developed for other disease indications that may have a positive effect on HIV eradication based on a growing understanding of the molecular mechanisms that control latent infection.
Oral Abstracts–State of the “Art” and Drug Resistance
This broad group of researchers explored the CD4 count among patients older than 16 years initiating ART in five continents. An increasing trend in the median CD4 count from 2002 to 2010 was similar globally, across low-income, lower middle-oncome, upper middle-income, and high-income countries. No country reached a median cell count of ≥350 cells/μL at ART initiation during the study period, and the count still remained below 200 cells/μL in low- and middle-income countries in 2010. In all except the high-income countries, the median counts were higher and increased to a greater extent in women than men.
This Phase 3 study directly compared the “Quad” once-daily regimen that combines the integrase inhibitor elvitegravir (EVG), the pharmacoenhancer cobicistat (COBI), emtricitabine (FTC), and tenofovir DF (TDF) with tri-therapy comprised of co-formulated efavirenz/emtricitabine/tenofovir DF as initial therapy for HIV infection. The researchers reported that the Quad therapy yielded similarly high results as the triple-drug regimen, with an improved safety profile, including favorable CNS, rash, and fasting lipid results.
Poster Abstracts–Compartment and Sanctuary Site Pharmacology
A study of ART-naïve patients treated with one of two drug regimens underwent duodenoscopic biopsies at baseline and at 9 months after the start of treatment to assess ART penetration into gastrointestinal-associated lymphoid tissue (GALT). The study revealed that there was limited penetration of some components of ART, despite extensive vascularity of the tissue, which may allow for residual HIV replication.
The aim of this study was to quantify the concentrations of the intracellular levels of tenofovir-diphosphate (TFV-DP) and emtricitabine-triphosphate (FTC-TP) in blood, rectal, and cervical cells at various time periods during and after drug administration. The study yielded several key conclusions: drug concentrations in blood were similar to levels seen in HIV-infected patients at which they have been shown to induce an antiviral effect; both drugs reach levels to support chemoprophylaxis in rectal and cervical tissue for prevention in men who have sex with men, women, and intravenous drug users, with especially high TFV-DP levels in rectal cells; and TFV-DP had a long half-life with slow accumulation, with FTC-TP having a shorter half-life with faster accumulation.
HCV Infection
Cost-Effectiveness of Protease Inhibitors
Chronic hepatitis C virus (HCV) affects about 3 million people in the U.S. and 180 million worldwide. The addition of new protease inhibitor (PI) therapies to standard treatment regimens can improve disease management, but they are costly and may not be similarly effective in all patients. Lie et al. evaluated the cost-effectiveness of PIs and of an interleukin (IL)-28B genotyping assay for identifying patients most likely to benefit from PIs. The IL-28B genotype predicts response to standard HCV therapy: people with a CC genotype tend to respond well to standard regimens, while those with a CT or TT genotype tend to achieve only a 30% sustained virologic response (SVR) rate with the addition of a PI. The study found that universal triple therapy (a standard regimen of pegylated interferon and ribavirin plus a PI) was cost-effective for treating patients with advanced liver fibrosis if the least expensive PIs are used. IL-28B guided triple therapy was also cost-effective in the same scenario described above and did not offer significant additional cost savings.
Source: Liu S, Cipriano LE, Holodnly M, et al. New Protease Inhibitors for the Treatment of Chronic Hepatitis C: A Cost-Effectiveness Analysis. Ann Intern Med 2012;156;279–290.